There are few documented instances in which human organs are able to respond to injury by complete and perfect replacement of the damaged parts. Under the appropriate conditions the adult digit is one such organ. The digit is composed of a diverse number of distinct cell types making up the various tissues of the digit (e.g. epidermis, nail, nailbed, dermis, adipose, bone), and in response to amputation, a perfect replica of the tip of the digit including the nail and fingerprint regenerates. This regeneration response is level-specific and only occurs following amputations at the level of the nailbed. An additional aspect of digit regeneration is that wound healing occurs without the deposition of scar tissue, whereas wound healing of amputations just proximal to the nailbed (regeneration-incompetent) results in scar tissue formation. Thus, digit amputation in mammals represents a model system to study both organ regeneration and scar-free wound healing. It is therefore surprising that there has been little interest in studying this remarkable phenomenon, despite the fact that the most frequent body part injured is the hand and that in the US approximately 19,00() people experience loss of a digit in any one year. The best model for digit regeneration is the mouse digit and using this system we have initiated the first molecular characterization of digit formation and regeneration. Digit regeneration is associated with the presence nailbed tissue at the wound and we show that two homeobox- containing genes (Msx1 and Msx2) are expressed by nailbed cells and also during regeneration. Recently both of these genes have been knockout in the lab of Dr. Richard Maas. In collaboration with Dr. Maas I propose to utilize these mutant strains to investigate the role of the nailbed and the Msx genes in the control of digit regeneration and wound healing. Because the Msx mutant mice do not survive to adulthood, we will conduct these experiments on digits that develop ectopically following exo-utero grafting of mutant digit rudiments onto wild type embryos. The specific aims include l) characterizing the regeneration-inducing capacity of nailbed tissue, 2) characterizing the role of nailbed cells in wound healing following amputation, 3) characterizing post-natal development, regenerative potential and wound healing of Msx1-/- mutant mice, Msx2-/- mutant mice, and Msx1-/-/Msx2-/-double mutant mice.